Immune Profiling and T Cell Research

1 CD8+ T Cell Exhaustion Atlas

  • Principal Investigator:: Multiple groups (NIH intramural)

  • Institution:: NIH / multi-centre

  • Contact/URL:: https://doi.org/10.1073/pnas.2415119121

  • Funder:: NIH intramural

  • Status:: Published 2025

  • Phase:: Observational (scRNA-seq atlas)

  • Cohort:: 28 ME/CFS patients + 30 sedentary controls; 336,269 T lymphoid cells analysed

  • Mechanism/Focus:: Single-cell transcriptomics of CD8+ T cells at baseline and after symptom provocation (exercise challenge). Identified transcriptional reprogramming toward exhaustion phenotypes, with altered effector, memory, and regulatory T cell subsets.

  • Primary Outcomes:: CD8+ T cells in ME/CFS show exhaustion-associated gene expression; exercise provocation amplifies the dysregulation

  • Estimated Completion:: Published

  • Publication Medium:: Proceedings of the National Academy of Sciences

  • Document Relevance:: Ch. 7 (immune dysfunction), Ch. 6 (energy metabolism—immune cell energetics), Ch. 22 (mechanistic studies)

T cell exhaustion was previously studied mainly in cancer and chronic viral infections. Its identification in ME/CFS opens a therapeutic avenue: checkpoint inhibitor-like approaches that reverse exhaustion might restore immune surveillance and reduce symptom burden (Mayer et al. 2025). The exercise provocation design is particularly valuable, as it captures the dynamic immune dysregulation underlying post-exertional malaise rather than just resting-state differences. The finding that monocyte fractions correlate with disease severity suggests potential for severity stratification.

2 Single-Cell Immune Remodelling in Long COVID–ME/CFS

  • Principal Investigator:: Shokrollah Elahi and collaborators

  • Institution:: University of Alberta, Canada

  • Contact/URL:: Science for ME discussion thread

  • Funder:: Institutional / CIHR

  • Status:: Published 2026

  • Phase:: Observational (scRNA-seq)

  • Cohort:: Female long COVID–ME/CFS patients (12 months post-acute infection) versus recovered individuals

  • Mechanism/Focus:: scRNA-seq of PBMCs examining monocyte, NK cell, and T cell compartments. Identified persistent immune remodelling 12 months after infection in those who developed ME/CFS but not in those who recovered.

  • Primary Outcomes:: Distinct monocyte polarisation, NK cell dysfunction, and T cell exhaustion patterns specific to ME/CFS development after COVID-19

  • Estimated Completion:: Published

  • Publication Medium:: Nature Communications

  • Document Relevance:: Ch. 7 (immune dysfunction), Ch. 14 Speculative Cross-Disease Connections (long COVID comparison)

This study complements the NIH T cell atlas (Section Immune Profiling and T Cell Research) by examining the transition from acute infection to chronic disease. The comparison of ME/CFS developers versus recoverers at the same time point (12 months) provides a natural experiment for identifying immune features that distinguish pathological from physiological post-infection states (Elahi et al. 2026).

3 IgG Immune Complexes Disrupting Cellular Energetics

  • Principal Investigator:: Bhupesh K. Prusty (senior), Zhihang Liu (first author)

  • Institution:: Multi-centre

  • Funder:: Institutional

  • Status:: Published February 2026

  • Phase:: Observational (in vitro)

  • Cohort:: ME/CFS (n=39–40), post-COVID ME/CFS (n=15–16), healthy controls (n=39–41), MS controls (n=11–20), systemic sclerosis (n=21)

  • Mechanism/Focus:: Isolated IgG complexes from ME/CFS patient sera and applied them to human umbilical vein endothelial cells (HUVECs). Demonstrated that ME/CFS-derived IgG induces mitochondrial fragmentation while maintaining ATP production (stress adaptation rather than energy collapse), triggers IL-1β secretion, and produces disease-specific proteomic signatures: post-COVID IgG enriched in hemostasis/clotting pathways, classic ME/CFS in extracellular matrix remodelling pathways.

  • Primary Outcomes:: IgG from ME/CFS patients causes mitochondrial fragmentation in endothelial cells; effect predominantly in female patients; maintained spare respiratory capacity with glycolytic compensation

  • Estimated Completion:: Published

  • Publication Medium:: Brain, Behavior, and Immunity – Health

  • Document Relevance:: Ch. 6 (energy metabolism), Ch. 7 (immune dysfunction—autoantibodies), Ch. 10 (endothelial dysfunction), Ch. 13 (integrative models)

This is among the strongest “transfer experiment” results in ME/CFS: applying patient-derived IgG to healthy endothelial cells recapitulates mitochondrial disruption and inflammatory activation, implicating humoral immune factors as causal rather than epiphenomenal (Liu et al. 2026). If replicated with purified IgG subfractions, it could identify specific autoantibody targets and converge with the daratumumab (Section Autoimmunity and Immunomodulation) and immunoadsorption (Section Autoimmunity and Immunomodulation) therapeutic approaches.

References

Elahi, Shokrollah et al. 2026. “Single-Cell Analysis Reveals Immune Remodeling of Monocytes, NK Cells, T Cell Exhaustion in Long COVID with ME/CFS.” Nature Communications.
Liu, Zhihang, Claudia Hollmann, Shreya Kalanidhi, Aeneas Grothey, Jan Lamerding, Ritika Bhargava, Hannah Graßhoff, et al. 2026. “Immunoglobulin G Complexes from Post-Infectious ME/CFS, Including Post-COVID ME/CFS Disrupt Cellular Energetics and Alter Inflammatory Marker Secretion.” Brain, Behavior, and Immunity – Health 52: 101187. https://doi.org/10.1016/j.bbih.2026.101187.
Mayer, Jillian et al. 2025. “Transcriptional Reprogramming Primes CD8+ T Cells Toward Exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2415119121.